In response to a stressor that threatens to disrupt an organism's homeostasis, the brain activates various neuropeptide-secreting systems to attempt to maintain the health of the animal. These adjustments include changes in behavioral state, such as an increase in locomotor activity, as well as changes in physiological state, such as an increase in heart rate, blood pressure, and body temperature. If the stress response is excessive and prolonged, as frequently occurs in the busy lives of Americans, the altered behavioral and physiological states can be deleterious and harmful. An excessive stress response can weaken the immune system and increase the risk of illness, obesity, and heart attacks. The neurobiological basis of the stress response is poorly understood. The most studied stress inducing neuropeptide is corticotropin-releasing factor (CRF), which initiates a series of biological events that stimulate the stress response in mammals. Interestingly, a pair of novel neuropeptides, the Hypocretins (Herts), also causes a heightened arousal in animals. The precise role of Hcrt cells in initiating the stress response is unknown, primarily due to the difficulty in observing and manipulating this relatively small population of neurons in the inferior surface of the brain. However, specific manipulation of Hcrt cells is now possible using the novel technique of photostimulation, a method by which we can specifically excite Hcrt neurons with high temporal precision. The purpose of this proposal is to use photostimulation technology to study a causal role between Hypocretin cell activation and the stress response. Our specific hypothesis is that stimulation of Hcrt neurons induces behaviors and physiological processes associated with the response to acute stressors by stimulating the release of CRF. We will study this hypothesis in three aims: (1) To determine if stimulation of Hcrt neurons is sufficient to promote behaviors associated with acute stress;(2) To determine if stimulation of Hcrt neurons is sufficient to promote autonomic physiological processes associated with stress;(3) To determine if stimulation of Hcrt neurons alters CRF cell activity, gene expression, and peptide release. PUBLIC HEALTH RELEVANCE Research aimed at exploring the neurobiological basis of stress may lead to the development of drugs and other treatments to relieve the negative symptoms of stress disorders. Hypocretins have recently been the target of drug design, and elucidating the role of these neuropeptides in the stress response could lead to novel therapeutics for stress disorders and related illnesses, as well as identify potential side effects for drugs that target the Hcrt system for other disorders.